Increasing health care costs and disturbing gaps in quality of care make it imperative to identify and implement the most effective and efficient health care services. This need for effectiveness research to guide practice and policy is especially pressing in mental health. The arrival rate of new mental health treatments far exceeds our ability to compare them in traditional clinical trials. Meeting this demand for timely and relevant evidence will require transformation of research to increase generalizability while reducing research time and expense. New infrastructure and innovative research methods will be necessary to accomplish that transformation. We propose to develop a Mental Health Research Network (MHRN) including nine established public domain research centers based in integrated not-for-profit health systems. These systems provide care to a diverse population of 10 million people in 11 states, and they share rich and compatible data resources to support a range of effectiveness research. Diversity of member demographics, insurance coverage, and organization of health services make this network an ideal environment for studying variation in care, comparing effectiveness and cost of treatments across practice environments, and studying dissemination and health policies. Participating research centers are experienced in a wide range of clinical areas and research methods. Three years of funding will support development of a core infrastructure for collaborative effectiveness research in mental health and completion of 4 research projects that leverage that infrastructure in specific clinical areas. The 4 research projects include the following: 1) An observational study of practice variation in high- and low-value care for mood disorders, 2) A pilot effectiveness trial of behavioral activation therapy for perinatal depression, 3) A geographically and ethnically diverse autism registry for effectiveness studies, and 4) Longitudinal analysis of SSRI warnings and suicidality in youth. Our long-term objectives are to expand the MHRN to include additional health systems and external investigators, to conduct multi-site observational and experimental studies of comparative effectiveness, to develop and evaluate methods for dissemination and implementation, and to become a national resource of research methods and effectiveness evidence for researchers, patients, providers and healthcare leaders.